The overall objective of this program is to improve the chemotherapy of human cancer. To acomplish that objective a coordinated series of multidisciplinary studies are conducted as follows: 1. Selected agents, synthesized within our Institute and from outside sources, are tested in established experimental tumor systems, in tumor cells in culture, and in special models for antitumor activity as well as in antiviral assays both in vitro and in mice. 2. Additional systems, new or new in our laboratory, are developed and utilized for antitumor tests, such as a rat colon carcinoma or models for metastatic brain tumors. We also investigate the action and effects of antitumor agents on immune systems. 3. To improve the usefulness of known chemotherapeutic agents we attempt the development of new combination therapy regimens including immunopotentiators. 4. Studies of the mechanism of therapeutic action of antitumor agents are aimed at elucidating primary biochemical lesions, the nature of resistance, and the factors responsible for therapeutic selectivity. In regard to selectivity, emphasis is placed on transport mechanisms, in particular, those concerned with the uptake and retention of antifols.